Early oral celecoxib prevents contracture and modulates capsular fibrosis in a validated model of post-traumatic arthrofibrosis

Abstract

BACKGROUND

Post-traumatic arthrofibrosis results from excessive joint capsule fibrosis. Current treatments are limited to physiotherapy or surgical release, and no reliable preventive therapy exists. Celecoxib may reduce stiffness, but its preventive effect on capsular arthrofibrosis remains unproven.

AIM

To evaluate the effect of oral celecoxib on joint contracture and posterior capsular fibrosis in a validated rat model.

METHODS

Forty 14-week-old female Sprague Dawley rats underwent right knee surgery including intra-articular injury, posterior capsule disruption and immobilization for 4 weeks, followed by 4 weeks of remobilization. Two groups (control and celecoxib) of 20 rats each were divided so that 10 rats were assessed for biomechanical contracture - measuring passive extension angle (PEA) at different torques and calculating elastic torque, stiffness, and energy absorbed - while the remaining 10 rats were used to quantify posterior capsule area and thickness and to evaluate fibrotic tissue using a semiquantitative scale. All measurements were performed in a blinded manner by engineers or pathologists. The celecoxib group received oral celecoxib (50 mg/kg/24 hours) for 2 weeks after surgery.

RESULTS

All rats gained weight appropriately and celecoxib was well tolerated. Operated knees in the celecoxib group showed greater PEA at higher torques [PEA-8 N·cm: 38.6° (95% confidence interval: 5.3-72.0), P = 0.026; PEA at failure: 84.4°, P = 0.015], higher failure torque (17.6 N·cm, P = 0.002) and higher elastic torque (14.9 N·cm, P = 0.009) compared to operated knees in the control group. Histologically, operated knees in the celecoxib group exhibited greater amount of fibrous connective tissue [1.5 interquartile range (IR): 1.25-1.0; P = 0.003], higher cellular density [1.0 (IR: 0.25-2.0); P = 0.027) and increased vascularity [1.0 (IR: 0.5-1.0); P = 0.030] compared to controls.

CONCLUSION

This study provides the first experimental evidence that early oral celecoxib can prevent or limit post-traumatic arthrofibrosis of capsular origin, reducing joint contracture and modulating posterior capsular fibrosis toward a more active, immature tissue phenotype.

Key Words: Post-traumatic arthrofibrosis; Joint stiffness; Celecoxib; Posterior capsular fibrosis; Rat model

Core Tip: Post-traumatic arthrofibrosis remains a challenging condition with limited preventive strategies. In this rat model, celecoxib reduced capsular fibrosis and improved biomechanical outcomes, suggesting a potential disease-modifying effect on fibrotic remodeling rather than solely providing symptomatic relief. These findings support further investigation of celecoxib as a preventive intervention for post-traumatic joint contracture and provide a rationale for future translational and clinical studies.

INTRODUCTION

Joint stiffness after traumatic or surgical injury is mainly caused by excessive joint capsule fibrosis (post-traumatic arthrofibrosis)[1-5]. Apart from early mobilization, no effective preventive therapy for post-traumatic arthrofibrosis is currently available.

Retrospective registry studies suggest that perioperative selective anti-inflammatory drugs may reduce arthrofibrosis and the need for manipulation under anesthesia[6,7]. Celecoxib selectively inhibits cyclooxygenase-2, reducing prostaglandin synthesis and downstream inflammatory signaling, and may prevent arthrofibrosis by inhibiting myofibroblast activation and post-inflammatory cytokines[8-11], as shown in other preclinical fibrotic models[12-15].

However, no study has conclusively demonstrated that oral celecoxib prevents post-traumatic arthrofibrosis of capsular origin. Previous reports focused on intra-articular adhesions or myogenic contracture and often lacked remobilization or severe injury, limiting their ability to distinguish transient stiffness from persistent capsular fibrosis[16,17]. Other celecoxib studies found no added benefit with oral administration, no superiority over placebo, or focused on late-stage arthrofibrosis[9,10,18]. To our knowledge, none of these studies demonstrated histological differences in the posterior capsule. This study aimed to demonstrate oral celecoxib’s effectiveness in preventing post-traumatic arthrofibrosis in a validated rat model, specifically assessing its effect on biomechanical joint contracture and on the histological features of posterior capsular fibrosis.

MATERIALS AND METHODS

Non-randomized, blinded, prospective controlled study

Forty 14-week-old female Sprague Dawley rats (mean weight 306 g) were assigned to control or celecoxib groups (n = 20 each). In each group, 10 rats were used for biomechanical and 10 for histological analyses (Figure 1). Animals were excluded due to death, surgical complications (using humane endpoints according to the 2020 AVMA guidelines), or specimen processing issues.

Figure 1 Flowchart showing the distribution of the initial sample, losses during follow-up and final sample by groups.

This study was approved by the Animal Experimentation Committee at our Institution (approval No. PROEX 227.6/23; 29/09/2023). Animals were housed according to institutional veterinary protocols [groups of four with ad libitum chow and water, under 12 hours light, constant temperature (21 ± 2 °C) and humidity (45% ± 10%), with enrichment]. Surgeries were performed under sevoflurane anesthesia with antibiotic prophylaxis and multimodal analgesia (bupivacaine and buprenorphine). Animals were assigned numbers within each cage and treatment and measurement order followed this numbering to minimize potential confounders.

Right knee (operated knee) received the experimental intervention as described by Owen et al[4] and validated by our group, while left knee served as internal control (non-operated). A validated post-traumatic arthrofibrosis model was used, including intra-articular injury, posterior capsular disruption and percutaneous knee immobilization in full flexion, as previously described[4,19,20]. Fluoroscopy was used to confirm knee immobilization and exclude iatrogenic fractures. After surgery, rats had free cage activity during a 4-week immobilization period. Celecoxib (50 mg/kg in 0.3 mL 5% glucose) was given orally once daily for 14 days by a single investigator; this dose is safe in rats due to their high hepatic metabolism[15,17]. In this study, celecoxib was administered immediately after injury, and therefore should be considered a preventive strategy, in contrast to therapeutic approaches aimed at treating already established fibrosis. Postoperative analgesia was provided with oral buprenorphine (0.4 mg/kg) for 48-72 hours after surgery, and was administered equally in all groups, so that no other anti-inflammatory drugs were used. By the end of the 4-week immobilization period, a second procedure was performed to remove the suture, with fluoroscopy first confirming full-flexion positioning. The knot was exposed through a small incision and cut, after which the rats began a 4-week remobilization period with free cage activity. At the end of remobilization, animals were euthanized with intraperitoneal pentobarbital and both knees were harvested by disarticulating the hip and ankle, preserving the femur-knee-tibia complex with all soft tissues except the skin.

Biomechanical and histological processing and evaluation were performed as previously described[4,20]. Briefly, for the biomechanical assessment, femoral and tibial ends were potted in polymethylmethacrylate and mounted on a 10 Nm dynamic load cell (Servosis Testing Machines, Madrid, Spain) to record torque during a single loading cycle until capsule failure, generating a passive extension angle (PEA; degrees) - torque (N·m) curve for each knee. Digital curve files were coded to ensure blinding. For histology, central and lateral sections were stained using standard paraffin-embedded histological techniques with hematoxylin-eosin and Masson’s trichrome, yielding four stained sections per knee. All animals assigned to histological analysis were included. Quantitative assessment of posterior capsule thickness and area was performed using digital image analysis in a blinded manner at low magnification (2 × objective) on representative non-overlapping fields[4,20].

A detailed characterization of posterior capsular fibrosis was performed using a semiquantitative scoring approach at 20× magnification, as commonly applied in preclinical joint stiffness models[9,18,21,22]. Amount of fibrosis, fibrosis density, cellular density, and number of blood vessels were graded on a four-tier scale: 0 (no increase compared to internal controls of normal tissue, change less than 15%), 1 (mild increase, 15%-50%), 2 (moderate increase, 50%-100%), and 3 (marked increase, greater than 100%). Cellular morphology was classified as round with nucleolus (0), round without nucleolus (1), or spindle-shaped (2). Cellular organization was categorized as aligned (0) or disorganized (2). All samples were independently evaluated in a blinded manner by two expert musculoskeletal pathologists, with discrepancies resolved by consensus.

Statistical analyses were performed using SPSS 30.0 (IBM, NY, United States). Sample size was calculated from the biomechanical study assuming a 5% type I error, 80% power, a minimum detectable difference of 20° (SD: 15°), and a 10% dropout rate, resulting in 10 rats per group. Since the knees cannot be reutilized for both histologic and biomechanical testing, the sample size was doubled to 20 rats per group (10 for biomechanical, 10 for histology). Normality was assessed with the Shapiro-Wilk test; normally distributed variables are reported as mean and SD, non-normal distributed were expressed as median and interquartile range. Qualitative variables were compared using χ² or Fisher’s exact tests. Independent quantitative variables were compared using Student’s t-test (normal) or Mann-Whitney U test (non-normal), and paired variables using repeated-measures analysis of variance with Bonferroni-adjusted pairwise comparisons when significant. Celecoxib efficacy in preventing contracture and fibrosis was assessed by comparing operated knees between control and treatment groups. Statistical significance was set at P < 0.05. No formal correction for multiple comparisons was applied, as biomechanical endpoints were prespecified and biologically interrelated. Results were interpreted considering consistency across related measures rather than isolated P values.

RESULTS

Baseline characteristics were comparable between groups, with no relevant differences in age, sex, or body weight at any timepoint (Supplementary Table 1). All animals were of the same strain, age, and sex and were housed under identical environmental conditions. All rats gained weight appropriately after surgery, and all daily oral doses of celecoxib were administered and well tolerated. A total of 3 rats (7.5%) were excluded: One in the control group died during the first week due to teeth overgrowth; and two in the celecoxib group: One died during anesthesia for immobilization removal and one was excluded due to a distal femur fracture during the first surgery. Additionally, five knees in the control group were excluded due to issues during processing, biomechanical testing, or histological fixation, resulting in 11 knees lost overall (13.8%) (Figure 1). Eleven animals (27.5%) experienced immobilization failure at removal due to suture breakage or loosening. These animals were included in an intention-to-treat analysis. Failure was more frequent in the celecoxib group, but the difference was not statistically significant (P = 0.093). In the control group, failures were associated with an initial immobilization angle below 140° of flexion (Supplementary Table 2).

Compared with controls, celecoxib-treated operated knees showed significantly greater PEA at higher torques and higher failure and elastic torque. No differences were observed at lower torques. Notably, PEA did not differ between operated and non-operated knees within the celecoxib group. In the control group, PEA-4, PEA-8, and PEA at failure were significantly lower in operated than in non-operated limbs, supporting the validity of the model (Table 1, Figure 2).

Figure 2 Grouped bar chart of biomechanical outcomes by groups. ^aP < 0.05. PEA: Passive extension angle.

Table 1 Comparative analysis of biomechanical outcomes by groups, mean ± SD/median (interquartile range).

	Control		Celecoxib		Efficacy of celecoxib: Operated control vs operated celecoxib	Control (operated vs non-operated)	Celecoxib (operated vs non-operated)
	Non-operated limb	Operated limb	Non-operated limb	Operated limb
PEA-2 (º)	136.7 ± 29.5	107.5 ± 11.6	122.9 ± 28.6	124.5 ± 28.6	P = 0.259	P = 0.065	P = 0.891
PEA-4 (º)	153.4 ± 24.0	112.8 ± 35.2	145.0 ± 35.5	136.5 ± 29.4	P = 0.129	P = 0.011	P = 0.566
PEA-8 (º)	159.1 ± 22.6	123.7 ± 34.0	167.1 ± 37.0	162.4 ± 34.8	P = 0.026	P = 0.044	P = 0.769
PEA-failure (º)	204.6 (33.6)	138.1 (33.4)	229.4 (17)	222.5 (24.6)	P = 0.015	P = 0.043	P = 0.247
Failure torque (N·cm)	18.4 ± 8.9	21.2 ± 8.9)	32.3 ± 9.9	38.8 ± 11.1	P = 0.002	P = 0.588	P = 0.187
Elastic torque (N·cm)	13.1 ± 8.9	19.8 ± 8.9	29.1 ± 11.7	34.7 ± 11.6	P = 0.009	P = 0.063	P = 0.294
Stiffness (N·cm/º)	0.3 (0.4)	0.5 (0.4)	0.6 (0.4)	0.8 (0.8)	P = 0.637	P = 0.293	P = 0.579
Energy (N·cm·º)	1.1 (1.4)	0.9 (2.4)	2.2 (1.8)	3.7 (2.2)	P = 0.050	P = 0.463	P = 0.089

PEA: Passive extension angle.

In central sections, celecoxib-treated operated knees showed a significant increase in fibrous connective tissue amount, cellular density and vascularity compared with controls, while no differences were observed in lateral sections. Quantitative assessment revealed no differences in posterior capsule in either section (Table 2, Figure 3).

Figure 3 Histological evaluation of celecoxib efficacy in central sections of operated knees. A-C: Control; D-F: Celecoxib-treated specimens. Panels are arranged by staining and magnification to facilitate direct comparison between control (A-C) and celecoxib-treated specimens (D-F). Masson’s trichrome-stained sections at 2× magnification (A and D) were used for quantitative assessment of posterior capsule area and thickness. Higher magnification images at 20× (B and E: Masson’s trichrome; C and F: Hematoxylin-eosin) illustrate representative fibrotic tissue. Asterisks indicate collagen-rich fibrotic areas. Orange arrows indicate fibroblast nuclei (elongated cells) and black arrows indicate blood vessels or capillaries. Celecoxib-treated posterior capsules exhibited a greater overall extent of fibrotic tissue (i.e., larger area of connective tissue involvement), along with increased cellular density and vascularity. In contrast, control specimens demonstrated a more limited fibrotic area, but with relatively denser collagen organization and lower cellular and vascular components. These findings were consistent with semiquantitative analyses (P < 0.05).

Table 2 Comparative analysis of histological outcomes by groups, median (interquartile range).

		Control		Celecoxib		Efficacy of celecoxib: Operated control vs operated celecoxib	Control (operated vs non-operated)	Celecoxib (operated vs non-operated)
		Non-operated limb	Operated limb	Non-operated limb	Operated limb
Quantitative evaluation
Capsule area (mm2)	C	1.65 (0.75)	2.90 (2.47)	1.98 (1.86)	2.98 (2.60)	P = 0.805	P = 0.007	P = 0.128
	L	1.76 (1.64)	2.21 (1.42)	2.21 (0.60)	2.30 (1.10)	P = 0.710	P = 0.097	P = 0.805
Capsule thickness (mm)	C	0.53 (0.33)	0.84 (0.53)	0.55 (0.61)	1.22 (0.714)	P = 0.209	P = 0.007	P = 0.011
	L	0.43 (0.29)	0.68 (0.75)	0.68 (0.40)	0.51 (0.32)	P = 0.535	P = 0.073	P = 0.710
Semi-quantitative evaluation
Amount of fibrosis	C	0.5 (1.25)		2 (1)		P = 0.003
	L	1 (2)		1 (1)		P = 0.638
Fibrosis density	C	1.5 (1)		1 (1)		P = 0.606
	L	2 (1)		2 (1)		P = 1.00
Cellular density	C	1 (0.25)		2 (2)		P = 0.027
	L	1 (0)		2 (1)		P = 0.275
Cellular organization (disorganized)	C	6 (100%)		4 (57.1%)		P = 0.192
	L	6 (85.7%)		5 (83.3%)		P = 1.00
Cellular morphology	C	1 (0.25)		1 (1)		P = 0.327
	L	1 (0)		1 (0)		P = 0.593
Number of blood vessels	C	1 (0.5)		2 (1)		P = 0.030
	L	1 (1)		1 (0)		P = 0.389

C: Central section; L: Lateral section.

DISCUSSION

To our knowledge, this is the first study to demonstrate a preventive effect of oral celecoxib on post-traumatic arthrofibrosis of capsular origin. This was achieved using a validated model that includes both biomechanical assessment and blinded quantitative and semi-quantitative histological analyses, while incorporating a remobilization period, which minimizes the influence of transient and reversible components of stiffness. Knees treated with celecoxib not only exhibited reduced joint contracture in biomechanical testing, but also showed more cellular and less mature fibrotic tissue in the posterior capsule than in controls, providing both functional and histological evidence of its preventive effect.

Our biomechanical assessment demonstrated that operated knees treated with celecoxib exhibited significantly reduced joint stiffness at higher torques as well as increased failure torque and elastic torque. These findings indicate that, under the same applied torque, celecoxib-treated knees achieve greater ranges of motion, with load-deformation curves that are more elastic and more resistant to capsular rupture, closely approximating physiological behavior. This interpretation is further supported by the absence of differences in biomechanical variables between operated and non-operated knees within the celecoxib-treated group. Additionally, immobilization failures were more frequent in the celecoxib group, though not statistically significant, while failures in controls were mainly linked to surgical technique. Some studies have suggested a preventive effect of oral celecoxib on joint stiffness. Ozawa et al[17] used a rat model and observed that celecoxib was effective in reduction of myogenic stiffness but it did not prevent capsular or arthrogenic stiffness. Li et al[16] demonstrated that celecoxib prevented intra-articular adhesion formation in a rabbit model. However, arthrogenic stiffness originating in the posterior capsule represents the most persistent component of post-traumatic arthrofibrosis[1,3,23-25]. Moreover, recent studies using experimental models based on arthrogenic stiffness have shown that certain drugs can reduce the contracture formation[10,26-29]. In this context, unlike our study, the studies by Li et al[16] and Ozawa et al[17] did not include a remobilization period. By omitting remobilization, transient components such as muscle contracture or intra-articular adhesions are not eliminated, potentially biasing the interpretation of the reported effect[3,30,31]. Additionally, in those studies biomechanical evaluations were performed indirectly, either using external anatomical landmarks or radiographs while applying force with a dynamometer, which provides lower precision compared to our method employing a dynamic load cell that allows direct and continuous quantification of torsional torque and extension angle[16,17]. Furthermore, the model employed by Ozawa et al[17] lacked a severe joint injury, resulting in a milder and potentially reversible contracture regardless of pharmacological treatment[3,30-33].

In the histological analyses, we demonstrated that the posterior capsule of operated knees treated with celecoxib exhibited a significantly greater amount of fibrosis, higher cellular density, and increased vascularity. These findings indicate that the fibrotic tissue in the celecoxib group was more extensive and, as reflected by its higher cellularity and vascularity, more “active”, as well as less organized and likely less mature. This pattern may be associated with reduced stiffness and greater tissue compliance compared to more densely organized collagen structures[34,35]. However, no differences were observed in quantitative measures such as capsular thickness or area, and these findings were based on semiquantitative assessment. Therefore, the term “greater fibrous connective tissue” should be interpreted with caution. Rather than indicating an increase in mature fibrotic tissue, these features may reflect a more cellular and vascular connective tissue with characteristics of early or immature remodeling, which could be less mechanically restrictive than dense, mature fibrosis. These findings are consistent with previous experimental evidence showing that celecoxib modulates fibroblast activity by reducing collagen synthesis and interfering with key profibrotic signaling pathways[8,9,11,12,15,16]. From a histological standpoint, previous studies have only reported that oral celecoxib prevented macroscopic muscular shortening or intra-articular adhesions[16,17]. In contrast, our study specifically targeted posterior capsular fibrosis, which is recognized as the main determinant of joint contracture[3,25,36]. Importantly, this interpretation remains speculative and cannot be confirmed without molecular or biochemical analyses (e.g., collagen type I/III ratio, α-spinal muscular atrophy expression, or transforming growth factor-β signaling), which were not performed in the present study.

In our study, early oral administration of celecoxib for preventive purposes resulted in positive outcomes. In contrast, previous studies have explored other routes of administration or with a therapeutic purpose, which, together with the studies already discussed, contributes to significant statistical heterogeneity in meta-analyses[37]. It is important to highlight that none of these studies have demonstrated microscopic changes in the histological evaluation of fibrosis. Salib et al[9] demonstrated that intra-articular administration of celecoxib prevented joint stiffness, but they did not observe any additional effect when oral celecoxib was combined with intra-articular administration. Nevertheless, their study design did not include a group exclusively evaluating oral administration, as it was used only as an adjuvant, and the dosage administered in their model (2.9-5.7 mg/kg every 48 hours) was considerably lower than the one used in our rat study (50 mg/kg every 24 hours). This higher dosage would largely overcome their concerns regarding hepatic metabolism, which is also high in this species[38]. Similarly, Limberg et al[18] demonstrated that intra-articular administration of celecoxib via a prolonged-release collagen membrane prevented joint stiffness. However, it is noteworthy that no significant differences were observed between the celecoxib-impregnated membrane and the placebo membrane[39,40]. Finally, Trousdale et al[10] demonstrated that intra-articular administration of celecoxib was superior to capsular release surgery, not as a preventive strategy but as a treatment once stiffness had already been established. Importantly, the dose of celecoxib used in this study (50 mg/kg/day) is higher than typical human-equivalent doses (approximately 200-400 mg/day)[41]. This reflects species-specific pharmacokinetics in rodents, including increased hepatic metabolism and drug clearance, but may also introduce potential off-target effects. Therefore, caution is warranted when translating these findings to clinical practice, and further studies are needed to determine whether similar antifibrotic effects can be achieved at clinically relevant doses.

Celecoxib was administered during the first two weeks after injury - when the rats remained immobilized - corresponding to the period in which myofibroblasts, the key drivers of arthrofibrosis, proliferate in the joint capsule[42]. Our findings indicate that the benefit is not limited to pain relief (which could allow earlier mobilization) but also includes modulation of capsular fibrosis and joint stiffness. Regarding doses of celecoxib, there is considerable heterogeneity in the experimental studies[9,13,14,41,43]. In rats, doses of 40-50 mg/kg once or twice daily have been used without reported toxicity, partly due to the higher hepatic metabolism characteristic of this species[15,17,38,44]. In clinical practice, celecoxib is approved for the symptomatic treatment of osteoarthritis and other conditions, highlighting the relevance of our findings relative to alternative administration routes[41]. It is generally regarded as safe and well-tolerated, with a lower incidence of gastroduodenal ulcers than non-selective anti-inflammatory drugs[41,45,46]; however, caution is advised in patients with pre-existing cardiovascular disease[47-49].

This study is not without limitations. During follow-up, 13.8% of knees were lost, all in the postoperative period. Although this resulted in a reduced sample size for some analyses, these losses are only slightly higher than those reported in preclinical models of post-traumatic joint stiffness[37]. Despite this, our procedure and oral celecoxib can be considered safe, as the rats gained weight appropriately after surgery and overall mortality was low. The lack of randomized allocation is explained by the study design: In the first phase, the objective was to validate the reproducibility of the experimental model, and the same animals were subsequently assigned to the control group in the second phase. This approach adhered to the principle of reduction in animal experimentation, in accordance with our institution’s veterinary ethics guidelines[20,50]. We believe this should not affect the interpretation of the results, as baseline characteristics within groups were comparable, including age, sex and body weight, and all animals were maintained under identical housing and experimental conditions, which likely mitigates the risk of selection bias. However, the study design also prevented the use of blinding and placebo in celecoxib administration, which could potentially introduce bias. To mitigate this, biomechanical and histological measurements were evaluated in a blinded manner. These concerns are widespread in animal experimentation, as the quality of the studies is often poor in terms of experimental design[51]. A relatively high rate of immobilization failure (27.5%) was observed, which may have introduced variability in the induction of arthrofibrosis. However, failure was not significantly different between groups and appeared to be mainly related to technical factors rather than to the intervention itself. Importantly, arthrofibrosis was consistently observed despite partial loss of immobilization, as demonstrated by the differences between operated and contralateral knees within each group. This suggests that partial immobilization may be sufficient to trigger the fibrotic response and that suture failure does not necessarily imply absence of arthrofibrosis. Although a formal sensitivity analysis was not performed, the consistency of the findings suggests that immobilization failure is unlikely to have substantially influenced the main results, but should be considered when interpreting the data. Given the number of biomechanical comparisons and the limited sample size, the possibility of type I error cannot be excluded. Finally, the conclusions regarding the modulation of fibrosis maturity are based on an evaluation using a semiquantitative scale. This approach is one of the most widely used histological techniques in preclinical research on joint stiffness, as it provides a general overview of the tissue and its architecture. Semiquantitative scales allow for a structured and reproducible assessment of the joint capsule and the degree of fibrosis by evaluating parameters such as thickness, cellular density, vascularization, and the proportion of connective tissue[9,18,21,22]. However, they also present important limitations, including the inherent subjectivity of the analysis, the low sensitivity for detecting subtle changes, and the reliance on the observer’s experience. Studies using the same staining method as ours have performed similar qualitative assessments with favorable results[21,52]. Nevertheless, other authors have employed complementary approaches to better characterize collagen and fibrosis, including biochemical quantifications and immunohistochemistry[18,21,22,43]. The absence of these methods in our study represents a limitation; however, this was partly mitigated by the independent and blinded evaluation performed by two pathologists specialized in musculoskeletal pathology, as well as by conducting the assessment in comparison with the contralateral non-operated knee to minimize intra-individual variability. Future studies should explore these more specific methods to provide deeper insight into tissue remodeling and therapeutic response.

CONCLUSION

In conclusion, this study provides the first experimental evidence that oral celecoxib administered in the early post-injury period can prevent or limit arthrogenic post-traumatic stiffness. Using a validated model with blinded biomechanical and histological analyses, we demonstrated that celecoxib not only reduces joint contracture but also modulates posterior capsular fibrous connective tissue, resulting in tissue that is more extensive, active and immature.